TRFR_HUMAN
ID TRFR_HUMAN Reviewed; 398 AA.
AC P34981; Q2M339;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1994, sequence version 1.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Thyrotropin-releasing hormone receptor;
DE Short=TRH-R;
DE AltName: Full=Thyroliberin receptor;
GN Name=TRHR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8395824; DOI=10.1006/bbrc.1993.2027;
RA Matre V., Karlsen H.E., Wright M.S., Lundell I., Fjeldheim K.,
RA Gabrielsen O.S., Larhammar D., Gautvik K.M.;
RT "Molecular cloning of a functional human thyrotropin-releasing hormone
RT receptor.";
RL Biochem. Biophys. Res. Commun. 195:179-185(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Pituitary;
RX PubMed=8396925; DOI=10.1006/bbrc.1993.2107;
RA Yamada M., Monden T., Satoh T., Satoh N., Murakami M., Iriuchijima T.,
RA Kakegawa T., Mori M.;
RT "Pituitary adenomas of patients with acromegaly express thyrotropin-
RT releasing hormone receptor messenger RNA: cloning and functional expression
RT of the human thyrotropin-releasing hormone receptor gene.";
RL Biochem. Biophys. Res. Commun. 195:737-745(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8243797; DOI=10.1016/0303-7207(93)90043-j;
RA Duthie S.M., Taylor P.L., Anderson L., Cook J., Eidne K.A.;
RT "Cloning and functional characterisation of the human TRH receptor.";
RL Mol. Cell. Endocrinol. 95:R11-R15(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7918619; DOI=10.1016/0167-4781(94)90046-9;
RA Hinuma S., Hosoya M., Ogi K., Tanaka H., Nagai Y., Onda H.;
RT "Molecular cloning and functional expression of a human thyrotropin-
RT releasing hormone (TRH) receptor gene.";
RL Biochim. Biophys. Acta 1219:251-259(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8703031; DOI=10.1074/jbc.271.36.22183;
RA Iwasaki T., Yamada M., Satoh T., Konaka S., Ren Y., Hashimoto K., Kohga H.,
RA Kato Y., Mori M.;
RT "Genomic organization and promoter function of the human thyrotropin-
RT releasing hormone receptor gene.";
RL J. Biol. Chem. 271:22183-22188(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pituitary;
RA Kopatz S.A., Aronstam R.S., Sharma S.V.;
RT "cDNA clones of human proteins involved in signal transduction sequenced by
RT the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-263.
RC TISSUE=Placenta;
RX PubMed=9886052; DOI=10.1046/j.1471-4159.1999.0720040.x;
RA Matre V., Hovring P.I., Orstavik S., Frengen E., Rian E., Velickovic Z.,
RA Murray-Mcintosh R.P., Gautvik K.M.;
RT "Structural and functional organization of the gene encoding the human
RT thyrotropin-releasing hormone receptor.";
RL J. Neurochem. 72:40-50(1999).
RN [9]
RP DISULFIDE BOND.
RX PubMed=8770906; DOI=10.1210/endo.137.7.8770906;
RA Cook J.V., McGregor A., Lee T., Milligan G., Eidne K.A.;
RT "A disulfide bonding interaction role for cysteines in the extracellular
RT domain of the thyrotropin-releasing hormone receptor.";
RL Endocrinology 137:2851-2858(1996).
RN [10]
RP FUNCTION, INVOLVEMENT IN CHNG7, VARIANTS CHNG7 17-ARG--SER-398 DEL AND
RP 115-SER--ALA-118 DELINS THR, AND CHARACTERIZATION OF VARIANTS CHNG7
RP 17-ARG--SER-398 DEL AND 115-SER--ALA-118 DELINS THR.
RX PubMed=9141550; DOI=10.1210/jcem.82.5.3918;
RA Collu R., Tang J., Castagne J., Lagace G., Masson N., Huot C., Deal C.,
RA Delvin E., Faccenda E., Eidne K.A., Van Vliet G.;
RT "A novel mechanism for isolated central hypothyroidism: inactivating
RT mutations in the thyrotropin-releasing hormone receptor gene.";
RL J. Clin. Endocrinol. Metab. 82:1561-1565(1997).
RN [11]
RP INVOLVEMENT IN CHNG7, AND VARIANT CHNG7 17-ARG--SER-398 DEL.
RX PubMed=19213692; DOI=10.1056/nejmc0808557;
RA Bonomi M., Busnelli M., Beck-Peccoz P., Costanzo D., Antonica F., Dolci C.,
RA Pilotta A., Buzi F., Persani L.;
RT "A family with complete resistance to thyrotropin-releasing hormone.";
RL N. Engl. J. Med. 360:731-734(2009).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, INVOLVEMENT IN CHNG7, VARIANT CHNG7 ARG-81,
RP AND CHARACTERIZATION OF VARIANT CHNG7 ARG-81.
RX PubMed=26735259; DOI=10.1210/jc.2015-3916;
RA Koulouri O., Nicholas A.K., Schoenmakers E., Mokrosinski J., Lane F.,
RA Cole T., Kirk J., Farooqi I.S., Chatterjee V.K., Gurnell M.,
RA Schoenmakers N.;
RT "A novel thyrotropin-releasing hormone receptor missense mutation (P81R) in
RT central congenital hypothyroidism.";
RL J. Clin. Endocrinol. Metab. 101:847-851(2016).
RN [13]
RP FUNCTION, INVOLVEMENT IN CHNG7, VARIANT CHNG7 THR-131, AND CHARACTERIZATION
RP OF VARIANT CHNG7 THR-131.
RX PubMed=28419241; DOI=10.1210/jc.2016-3977;
RA Garcia M., Gonzalez de Buitrago J., Jimenez-Roses M., Pardo L.,
RA Hinkle P.M., Moreno J.C.;
RT "Central hypothyroidism due to a TRHR mutation causing impaired ligand
RT affinity and transactivation of Gq.";
RL J. Clin. Endocrinol. Metab. 102:2433-2442(2017).
CC -!- FUNCTION: Receptor for thyrotropin-releasing hormone (TRH). Upon ligand
CC binding, this G-protein-coupled receptor triggers activation of the
CC phosphatidylinositol (IP3)-calcium-protein kinase C (PKC) pathway.
CC {ECO:0000269|PubMed:26735259, ECO:0000269|PubMed:9141550}.
CC -!- INTERACTION:
CC P34981; Q86Z23: C1QL4; NbExp=3; IntAct=EBI-18055230, EBI-12062109;
CC P34981; P21964: COMT; NbExp=3; IntAct=EBI-18055230, EBI-372265;
CC P34981; P52803: EFNA5; NbExp=3; IntAct=EBI-18055230, EBI-1753674;
CC P34981; Q96D05-2: FAM241B; NbExp=3; IntAct=EBI-18055230, EBI-12118888;
CC P34981; P29033: GJB2; NbExp=3; IntAct=EBI-18055230, EBI-3905204;
CC P34981; Q9Y5U9: IER3IP1; NbExp=3; IntAct=EBI-18055230, EBI-725665;
CC P34981; Q0D2K0: NIPAL4; NbExp=3; IntAct=EBI-18055230, EBI-9550165;
CC P34981; I3L0A0: PEDS1-UBE2V1; NbExp=3; IntAct=EBI-18055230, EBI-12213001;
CC P34981; Q9NP94: SLC39A2; NbExp=3; IntAct=EBI-18055230, EBI-12898013;
CC P34981; Q9NUM3: SLC39A9; NbExp=3; IntAct=EBI-18055230, EBI-2823239;
CC P34981; Q8IVJ1: SLC41A1; NbExp=3; IntAct=EBI-18055230, EBI-12266234;
CC P34981; Q9UIK5: TMEFF2; NbExp=3; IntAct=EBI-18055230, EBI-11423693;
CC P34981; A2RU14: TMEM218; NbExp=3; IntAct=EBI-18055230, EBI-10173151;
CC P34981; Q8WW34-2: TMEM239; NbExp=3; IntAct=EBI-18055230, EBI-11528917;
CC P34981; Q9Y385: UBE2J1; NbExp=3; IntAct=EBI-18055230, EBI-988826;
CC P34981; Q96EC8: YIPF6; NbExp=3; IntAct=EBI-18055230, EBI-751210;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26735259};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- DISEASE: Hypothyroidism, congenital, non-goitrous, 7 (CHNG7)
CC [MIM:618573]: A form of central hypothyroidism, a disorder
CC characterized by sub-optimal thyroid hormone secretion, due to
CC insufficient stimulation by thyrotropin of an otherwise normal thyroid
CC gland. It may be caused by congenital or acquired disorders of the
CC pituitary gland or hypothalamus. CHNG7 is a congenital, autosomal
CC recessive form characterized by normal-to-low T4 and normal-to-high
CC thyrotropin levels, and reduced or absent pituitary responsiveness to
CC thyrotropin-releasing hormone. Patients may exhibit short stature,
CC growth retardation, and delayed bone age, as well as lethargy or
CC fatigue. {ECO:0000269|PubMed:19213692, ECO:0000269|PubMed:26735259,
CC ECO:0000269|PubMed:28419241, ECO:0000269|PubMed:9141550}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; D16845; BAA04120.1; -; mRNA.
DR EMBL; X75071; CAA52965.1; -; mRNA.
DR EMBL; X72089; CAA50979.1; -; mRNA.
DR EMBL; S75283; AAB32222.1; -; Genomic_DNA.
DR EMBL; S75281; AAB32222.1; JOINED; Genomic_DNA.
DR EMBL; D85376; BAA12796.1; -; Genomic_DNA.
DR EMBL; AY493373; AAR84356.1; -; mRNA.
DR EMBL; BC105045; AAI05046.1; -; mRNA.
DR EMBL; BC113360; AAI13361.1; -; mRNA.
DR EMBL; AJ011701; CAA09746.1; -; Genomic_DNA.
DR CCDS; CCDS6311.1; -.
DR PIR; S40682; JN0708.
DR RefSeq; NP_003292.1; NM_003301.5.
DR RefSeq; XP_011515565.1; XM_011517263.2.
DR AlphaFoldDB; P34981; -.
DR SMR; P34981; -.
DR BioGRID; 113052; 20.
DR IntAct; P34981; 17.
DR STRING; 9606.ENSP00000430711; -.
DR BindingDB; P34981; -.
DR ChEMBL; CHEMBL1810; -.
DR DrugBank; DB09421; Protirelin.
DR DrugCentral; P34981; -.
DR GuidetoPHARMACOLOGY; 363; -.
DR TCDB; 9.A.14.1.4; the g-protein-coupled receptor (gpcr) family.
DR GlyGen; P34981; 2 sites.
DR iPTMnet; P34981; -.
DR PhosphoSitePlus; P34981; -.
DR BioMuta; TRHR; -.
DR DMDM; 464921; -.
DR MassIVE; P34981; -.
DR PaxDb; P34981; -.
DR PeptideAtlas; P34981; -.
DR PRIDE; P34981; -.
DR Antibodypedia; 13449; 308 antibodies from 31 providers.
DR DNASU; 7201; -.
DR Ensembl; ENST00000311762.2; ENSP00000309818.2; ENSG00000174417.3.
DR Ensembl; ENST00000518632.2; ENSP00000430711.2; ENSG00000174417.3.
DR GeneID; 7201; -.
DR KEGG; hsa:7201; -.
DR MANE-Select; ENST00000518632.2; ENSP00000430711.2; NM_003301.7; NP_003292.1.
DR UCSC; uc003ymz.5; human.
DR CTD; 7201; -.
DR DisGeNET; 7201; -.
DR GeneCards; TRHR; -.
DR HGNC; HGNC:12299; TRHR.
DR HPA; ENSG00000174417; Tissue enriched (brain).
DR MalaCards; TRHR; -.
DR MIM; 188545; gene.
DR MIM; 618573; phenotype.
DR neXtProt; NX_P34981; -.
DR OpenTargets; ENSG00000174417; -.
DR Orphanet; 99832; Resistance to thyrotropin-releasing hormone syndrome.
DR PharmGKB; PA36979; -.
DR VEuPathDB; HostDB:ENSG00000174417; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT01040000240430; -.
DR HOGENOM; CLU_009579_6_5_1; -.
DR InParanoid; P34981; -.
DR OMA; SKTWRND; -.
DR OrthoDB; 1255241at2759; -.
DR PhylomeDB; P34981; -.
DR TreeFam; TF326170; -.
DR PathwayCommons; P34981; -.
DR Reactome; R-HSA-375276; Peptide ligand-binding receptors.
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR SignaLink; P34981; -.
DR SIGNOR; P34981; -.
DR BioGRID-ORCS; 7201; 9 hits in 1059 CRISPR screens.
DR ChiTaRS; TRHR; human.
DR GeneWiki; Thyrotropin-releasing_hormone_receptor; -.
DR GenomeRNAi; 7201; -.
DR Pharos; P34981; Tclin.
DR PRO; PR:P34981; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; P34981; protein.
DR Bgee; ENSG00000174417; Expressed in calcaneal tendon and 16 other tissues.
DR Genevisible; P34981; HS.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004997; F:thyrotropin-releasing hormone receptor activity; IBA:GO_Central.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR002120; TRH_rcpt_1.
DR PANTHER; PTHR46061; PTHR46061; 1.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR00751; THYROLIBRINR.
DR PRINTS; PR01846; TRHRFAMILY.
DR SMART; SM01381; 7TM_GPCR_Srsx; 1.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Congenital hypothyroidism; Disease variant; Disulfide bond;
KW G-protein coupled receptor; Glycoprotein; Membrane; Receptor;
KW Reference proteome; Transducer; Transmembrane; Transmembrane helix.
FT CHAIN 1..398
FT /note="Thyrotropin-releasing hormone receptor"
FT /id="PRO_0000070187"
FT TOPO_DOM 1..28
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 29..51
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 52..61
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 62..83
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 84..99
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 100..121
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 122..144
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 145..168
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 169..193
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 194..215
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 216..266
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 267..288
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 289..296
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 297..319
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 320..398
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT CARBOHYD 3
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 10
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 98..179
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521,
FT ECO:0000269|PubMed:8770906"
FT VARIANT 10
FT /note="N -> K (in dbSNP:rs5774)"
FT /id="VAR_011857"
FT VARIANT 17..398
FT /note="Missing (in CHNG7; loss of thyrotropin-releasing
FT hormone receptor activity)"
FT /evidence="ECO:0000269|PubMed:19213692,
FT ECO:0000269|PubMed:9141550"
FT /id="VAR_083281"
FT VARIANT 81
FT /note="P -> R (in CHNG7; loss of thyrotropin-releasing
FT hormone receptor activity; no effect on localization to
FT plasma membrane)"
FT /evidence="ECO:0000269|PubMed:26735259"
FT /id="VAR_083282"
FT VARIANT 115..118
FT /note="SITA -> T (in CHNG7; loss of thyrotropin-releasing
FT hormone receptor activity)"
FT /evidence="ECO:0000269|PubMed:9141550"
FT /id="VAR_083283"
FT VARIANT 131
FT /note="I -> T (in CHNG7; decreased affinity for TRH)"
FT /evidence="ECO:0000269|PubMed:28419241"
FT /id="VAR_083284"
FT VARIANT 168
FT /note="I -> M (in dbSNP:rs13306060)"
FT /id="VAR_049450"
SQ SEQUENCE 398 AA; 45085 MW; FE920B5F2E933D3E CRC64;
MENETVSELN QTQLQPRAVV ALEYQVVTIL LVLIICGLGI VGNIMVVLVV MRTKHMRTPT
NCYLVSLAVA DLMVLVAAGL PNITDSIYGS WVYGYVGCLC ITYLQYLGIN ASSCSITAFT
IERYIAICHP IKAQFLCTFS RAKKIIIFVW AFTSLYCMLW FFLLDLNIST YKDAIVISCG
YKISRNYYSP IYLMDFGVFY VVPMILATVL YGFIARILFL NPIPSDPKEN SKTWKNDSTH
QNTNLNVNTS NRCFNSTVSS RKQVTKMLAV VVILFALLWM PYRTLVVVNS FLSSPFQENW
FLLFCRICIY LNSAINPVIY NLMSQKFRAA FRKLCNCKQK PTEKPANYSV ALNYSVIKES
DHFSTELDDI TVTDTYLSAT KVSFDDTCLA SEVSFSQS
